Process for the preparation of substituted pyrimidines

ABSTRACT

The invention relates to a process for the preparation of substituted pyrimidines of formula I,                    
     wherein 
     R 1 , R 2 , R 3 , R 4  and X are as defined in claim 1, 
     which comprises reacting an amidine of formula II,                    
     or a salt thereof, with a  3,3 -disubstituted vinylcarbonyl compound of formula III                    
     wherein L represent a halogen atom or a group of formula —X—R 2 , 
     (a) in an inert solvent, in the presence of a base and a compound of formula IV 
     
       
         H—X—R 2   (IV) 
       
     
     in the event that L represent a halogen atom, or 
     (b) in an inert solvent and in the presence of a base, in the event that L represents a group of formula —X—R 2 .

This application is a division of application Ser. No. 09/547,666 filedApr. 12, 2000, now U.S. Pat. No. 6,281,358, which claims the benefit ofProvisional application Ser. No. 60/129,462, Apr. 15, 1999, and claimsthe benefit of Provisional application Ser. No. 60/139,356, filed Jun.15, 1999.

BACKGROUND OF THE INVENTION

The present invention relates to an improved process for the preparationof substituted pyrimidines.

Pyrimidines, which are substituted in the 4-position by a hydrocarbyloxyor hydrocarbylthio group are of great commercial interest as highlyeffective pesticides or pharmaceuticals. U.S. Pat. No. 3,498,984discloses 2-phenyl-4-thiopyrimidines with interesting pharmaceuticalproperties. U.S. Pat. No. 5,824,624 describes herbicidal compositionscomprising 2-phenyl-4-oxypyrimidines. The International PatentApplications WO 98/40379 and WO 98/56789 disclose herbicidal4-oxypyrimidines, in which a 5-membered heteroaromatic group is attachedto the 2-position position of the pyrimidine moiety.

These compounds can be prepared for example in a multi-step processincluding the steps of treating a benzamidine hydrochloride with asubstituted acetylacetate in the presence of a strong base to form a2-phenylpyrimid-4-one, which is subsequently treated with a halogenatingagent, in particular a phosphoryl halide to yield a4-halo-2-phenylpyrimidine, which is reacted with an alcohol or athioalcohol.

However, this process cannot be used for manufacture of relatively largequantities on an industrial scale due to the high risk of uncontrollableheat generation during the aqueous work up of the halogenation step.

W. Schroth et al., disclose the preparation of 1,3-thiazin-6-thiones bycondensation of 3,3-dichloroacrolein and thioamides in the presence oftrifluoroborane.

However, there is no motivation to apply this reaction on themanufacture of substituted pyrimidines, especially, sincetrifluoroborane is not applicable in large scale productions.

SUMMARY OF THE INVENTION

The present invention provides an effective and efficient process forthe preparation of substituted pyrimidines of formula I,

wherein

R¹ and R² each independently represent an optionally substituted alkyl,cycloalkyl, phenyl or heteroaryl group,

R³ and R⁴ each independently represent a hydrogen atom or an optionallysubstituted alkyl or phenyl group, and

X represents O or S.

which comprises

reacting an amidine of formula II,

or a salt thereof, wherein R¹ has the meaning given for formula I, witha 3,3-disubstituted vinylcarbonyl compound of formula III

wherein R³ and R⁴ have the meaning given, and

L represent a halogen atom or a group of formula —X—R²,

(a) in an inert solvent, in the presence of a base and a compound offormula IV

H—X—R²  (IV)

 wherein X and R² have the meaning given, in the event that L representa halogen atom, or

(b) in an inert solvent and in the presence of a base, in the event thatL represents a group of formula —X—R².

It is, therefore, an object of the present invention to provide anefficient new process for the preparation of substituted pyrimidines.

Other objects and advantages of the present invention will be apparentto those skilled in the art from the following description and theappended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

When any groups are designated as being optionally substituted, thesubstituent groups which are optionally present may be any of thosecustomarily employed in the modification and/or development ofpesticidal/pharmaceutical compounds and are especially substituents thatmaintain or enhance the herbicidal activity associated with thecompounds of the present invention, or influence persistence of action,soil or plant penetration, or any other desirable property of suchherbicidal compounds. There may be one or more of the same or differentsubstituents present in each part of the molecules.

In relation to moieties defined above as comprising an optionallysubstituted alkyl or cycloalkyl group, specific examples of suchsubstituents include phenyl, halogen atoms, nitro, cyano, hydroxyl,C₁₋₄-alkoxy, C₁₋₄-haloalkoxy and C₁₋₄-alkoxycarbonyl groups.

In relation to moieties defined above as comprising an optionallysubstituted phenyl group or heteroaryl group, optional substituentsinclude halogen, especially fluorine, chlorine and bromine atoms, andnitro, cyano, amino, hydroxyl, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-haloalkyl,C₁₋₄-haloalkoxy, C₁₋₄-haloalkylthio and halosulfanyl groups such as SF₅.1 to 5 substituents may suitably be employed, 1 to 2 substituents beingpreferred. Typically haloalkyl, haloalkoxy and haloalkylthio groups aretrifluoromethyl, trifluoromethoxy, difluoromethoxy andtrifluoromethylthio groups.

In general terms, unless otherwise stated herein, the term alkyl as usedherein with respect to a radical or moiety refer to a straight orbranched chain radical or moiety. As a rule, such radicals have up to10, in particular up to 6 carbon atoms. Suitably an alkyl moiety hasfrom 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms. Apreferred alkyl moiety is the methyl or especially the ethyl group.

In general terms, unless otherwise stated herein, the term cycloalkyl asused herein with respect to a radical or moiety refers to a cycloalkylradical which has up to 10, in particular up to 8 carbon atoms. Suitablya cycloalkyl moiety has from 3 to 6 carbon atoms, preferably from 3 or 6carbon atoms. A preferred cycloalkyl moiety is the cyclopropyl,cyclopentyl and the cyclohexyl group.

In general terms, unless otherwise stated herein,the term heteroaryl asused herein with respect to a radical or moiety refers to a nitrogencontaining 5- or 6-membered heteroaromatic radical or moiety. As a rule,such radicals exhibit at least one nitrogen atom and in the case of thefive-membered radicals optionally one oxygen or sulfur atom; they arepreferably selected from the 5-membered azoles, diazoles, triazoles,thiazoles, isothiazoles, thiadiazoles, in particular pyrrole andpyrazole and the 6-membered azines and diazines, in particular pyridine,pyrimidine, pyridazine and pyrazine.

In a preferred embodiment R¹ represents an optionally substitutedphenyl, pyrid-3-yl, pyridazine-2-yl, pyrazine-3-yl, thiazol2-yl,oxazol-2-yl, 1,3,4-thiadiazol-2-y, 1,2,4-oxadiazol-2-yl,1,3,4-oxadiazol-2-yl, pyrazol-1-yl or C₃₋₆ cycloalkyl group.

In a preferred embodiment R² represents an optionally substitutedphenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4yl, pyrazol-5-yl, pyridazine-2-ylor C₃₋₆ cycloalkyl group.

The groups R¹ and R² each independently are preferable substituted byone or more alkyl, fluoroalky, alkoxy or fluoroalkoxy group.

Suitable bases are weak organic or inorganic bases, preferably alkalihydrogencarbonates, such as sodium hydrogencarbonate, alkali carbonates,such as potassium carbonate or sodium carbonate, and tertiary amines,such as pyridine or triethylamine.

Further preferred embodiments of the process according to the presentinvention are a processes wherein:

the reaction is carried out in the presence of a base selected from thegroup consisting of, alkali carbonates and tertiary amines, inparticular potassium carbonate or sodium carbonate;

the amidine of formula II to 3,3-disubstituted vinylcarbonyl compound offormula III molar ratio is from 1:5 to 1:0.5, in particular from 1:1.5to 1:0.7, most preferred from 1:1.1 to 1:0.9;

the reaction step further comprises stirring a mixture consistingessentially of the amidine of formula II, the 3,3-disubstitutedvinylcarbonyl compound of formula III, an inert diluent, a base and anoptionally substituted alcohol, thioalcohol, phenol or thiophenol at atemperature from 0° C. to 150° C., preferably from 60° C. to 145° C., inparticular from 80° C. to 140° C., most preferred at about the boilingpoint of the diluent;

the inert diluent is selected from the group consisting of acetonitril,benzene, toluene, xylene, hexane, cyclohexane, dichloromethane,tetrachloromethane, diethylether, diisopropylether,tert-butylmethylether, 2,2-dimethoxypropane, dimethoxyethane,diethoxyethane, tetrahydrofuran, tetrahydropyran, dimethylformamide,dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and dioxane,and a mixture thereof, in particular toluene, dimethoxyethane oracetonitril;

R¹ represents a phenyl group which is substituted by at least onehalogen atom, or at least one alkyl, alkoxy, haloalkyl or haloalkoxygroup, in particular a phenyl group which is substituted by one or twochlorine or fluorine atoms, or one or two C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄fluoroalkyl or C₁₋₄ fluoroalkoxy groups, R¹ is most preferably a4-trifluoromethylphenyl, difluoromethoxypyrid-2-yl or1-methyl-3-triflouromethylpyrazol 1-methyl-3-trifluoromethylpyrazol-5-ylgroup;

R¹ and R² each independently represent a phenyl group which issubstituted by at least one halogen atom, and/or at least one alkyl,alkoxy, haloalkyl or haloalkoxy group, X represents O, and whichcomprises that the reaction step is carried out in the presence of aphenol, which is substituted by at least one halogen atom, and/or atleast one alkyl, alkoxy, haloalkyl or haloalkoxy group, in particular aphenol which is substituted by one or two chlorine or fluorine atoms, orone or two C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ fluoroalkyl or C₁₋₄fluoroalkoxy groups, most preferred a 3-trifluoromethylphenol;

wherein the 3,3-disubstituted vinylcarbonyl compound of formula III is3,3-dichloroacrolein.

The compounds of formula II or the salts thereof are preferablyoptionally substituted benzamidines or benzamidinum salts, mostpreferred 4-trifluoromethylbenzamidine, which can be prepared fromcommercially available optionally substituted benzonitriles, inparticular 4-trifluoromethylbenzonitril, by addition of ammonia orammonium salts.

Preferred benzamidinium salts are chlorides, sulfates, nitrates andcarboxylates, in particular acetates and thioglycolates.

The 3,3-disubstituted vinylcarbonyl of formula III, wherein L representsa halogen atom are commercially available or can be prepared by reactionof tetrahalometharies with vinylethers.

In a preferred embodiment of this invention, the1,1,1,3-tetrahalo-3-alkoxypropane obtained in this reaction can behydrolysed in-situ to obtain the corresponding vinylcarbonyl compound offormula III, which is subsequently reacted, preferably without furtherisolation and/or purification steps, i.e., in a one-pot-synthesis, withthe compound of formual II.

The 3,3-disubstituted vinylcarbonyl of formula III, wherein L representsa group of formula —X—R^(2,) can be prepared by reaction of a compoundof formula III, wherein L represents a halogen atom with a compound offormula IV

H—X—R²  (IV)

optionally in the presence of a base.

As a rule the reaction between the amidine of formula II, the3,3-disubstituted vinyl carbonyl compound of formula III and optionallythe alcohol, phenol, thioalcohol or thiophenol is carried out atelevated temperatures, preferably between 35° C. and 150° C., inparticular between 80° C. and 145° C., most preferred at boiling pointof the diluent.

The crude product obtained can be purified according to standard methodsfor example by distillation in vacuo, chromatographic methods orcrystallization.

The reaction is as a rule completed within 5 to 50 hours, in particular10 to 25 hours.

In a particularly preferred embodiment of the process according to thisinvention 3,3-dichloroacrolein (1 mole) optionally diluted with an inertdiluent, in particular acetonitril, is added to a mixture consisting ofa benzamidine of formula II, wherein R¹ is a an optionally substitutedphenyl group, in particular 4-trifluoromethylbenzamidine (1 mole), anoptionally substituted phenol, in particular 3-trifluoromethylphenol(1.1 moles), potassium carbonate (3 to 5 moles) and a diluent, which isstirred under reflux. The reaction mixture is stirred for 10 to 40 hoursunder reflux. The reaction mixture is stirred for 10 to 40 hours underreflux and subsequently cooled down to ambient temperature, andfiltered. The organic phase is concentrated in vacuo. The residue iswashed with an organic solvent and the solvent is distilled off. Theresidue is purified by chromatography.

The compounds of formula 1 obtainable according to the process accordingthis invention are partly known and partly novel. The invention relatesalso to the novel compounds of formula 1A,

wherein R³ and R⁴ have the meaning given for formula 1, and R¹represents an optionally substituted C₃₋₈ cycloalkyl or pyrazin-2-ylgroup. R⁵ represents a halogen atom or a haloalkyl or haloalkoxy group,and W—V represents N—CH, S—CH, N—CH—CH, CH—CH—CH or N—N(R⁶), in which R⁶represents a C₁₋₄ alkyl group.

In order to facilitate a further understanding of the invention, thefollowing illustrative examples are presented. The invention is notlimited to the specific embodiments described or illustrated, butencompasses the full scope of the appended claims.

EXAMPLE 1 Preparation of4-(3-Triflouromethylphenoxy)-2-(4-Triflouromethylphenyl)-Pyrimidine

3,3-Dichloroacrolein (10 mmoles) diluted with acetonitril (50 ml), isslowly added to a mixture consisting of a 4-trifluoromethylbenzamidine(10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate(40 mmoles) and acetonitril (100 ml), which is stirred under reflux.When the addition of 3,3-dichloroacrolein is completed additional4-trifluoromethylbenzamidine (0.5 mmoles) is added. The reaction mixtureis stirred for 20 hours under reflux and subsequently cooled down toambient temperature and filtered through silica. The organic phase iswashed with ethyl acetate and concentrated in vacuo. The residuepurified by chromatography on Al₂O₃ (petrol ethers/ethyl acetate: 2/1)to yield 3.25 g (85%) of the pure product having a melting point of66-67° C.

Analogously are prepared3-methyl-4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine,5-4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine,4-phenoxy-2-(4-trifluoromethylphenyl)pyrimidine

EXAMPLES 2 TO 8 Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Trifluoromethylphenyl)-Pyrimidine,

Analogously to example 1 4-trifluoromethylbenzamidine or the saltsthereof are reacted with 3,3-dichloroacrolein in the presence of3-trifluoromethylphenol in different solvents at different temperatures

The reactants and solvents, the reaction temperature and yields areshown in table 1 in which the following abbreviations have been used:

TFBA 4-trifluoromethylbenzamidine TFBA * HCl4-trifluoromethylbenzamidine hydrochloride TFBA * Ac4-trifluoromethylbenzamidinium acetate TFBA * TG4-trifluoromethylbenzamidinium thioglycolate TBME tert-butylmethyletherDME dimethoxyethane

TABLE I Examples 2 to 8 Example starting material solvent temperatureYield (%) 2 TFBA acetonitril reflux 85 3 TFBA DME reflux 85 4 TFBAtoluene 90° C. 72 5 TFBA TBME reflux 39 6 TFBA * HCl DME reftux 84 7TFBA * Ac DME reflux 81 8 TFBA * TG DME reflux 47

EXAMPLE 9 Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Trifluoromethylphenyl)-Pyrimidine

A mixture of 3,3-bis-(3-trifluoromethylphenoxy)-acrolein (10 mmoles),4-trifluoromethylbenzamidine (10 mmoles), potassium carbonate (10mmoles) and acetonitril (100 ml), is stirred at 80° C. for four hours.The reaction mixture is cooled down to ambient temperature and filteredthrough silica. The organic phase is washed with ethyl acetate andconcentrated in vacuo. The residue is purified by chromatography onAl₂O₃ (petrol ethers/ethyl acetate: 2/1) to yield 3.06 g (80%) of thepure product having a melting point of 66° C.

EXAMPLE 10 Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Trifluoromethylphenyl)-Pyrimidine

3-Trifluoromethylphenol (5 mmoles) and subsequently 3,3-dichloroacrolein(5 mmoles) are added to a mixture consisting of a4-trifluoromethylbenzamidinium acetate (5 mmoles), sodium carbonate (40mmoles) and acetonitril (35 ml), which is stirred under reilux. Thereaction mixture is stirred for 20 hours under reflux and subsequentlycooled down to ambient temperature and filtered through silica. Theorganic phase is washed with ethyl acetate and concentrated in vacuo.The residue is purified by chromatography on Al₂O₃ (petrol ethers/ethylacetate: 2/1) to yield 1.1 g (60%) of the pure product having a meltingpoint of 66-67° C.

EXAMPLE 11 Enhanced Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Trifluoromethylphenyl)-Pyrimidine

Water (20 mmoles) is added to a solution of1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25ml). The reaction mixture is stirred for 2 h under reflux. The resultingmixture is slowly added to a mixture consisting of a4-trifluoromethylbenzamidine hydrochloride (10 mmoles),3-trifluoromethylphenol (11 mmoles), potassium carbonate (60 mmoles) anddimethoxyethane (50 ml), which is stirred under reflux. When theaddition of 3,3-dichloroacrolein solution is completed additional4-trifluoromethylbenzamidine hydrochloride (1 mmoles) is added. Thereaction mixture is stirred for 2 hours under reflux and subsequentlycooled down to ambient temperature, filtered through silica, and theorganic phase is concentrated in vacuo. The residue is purified bychromatography on SiO₂ (petrol ethers/diisopropylether: 6/1) to yield3,07 g (80%) of the product having a melting point of 66-67° C.

EXAMPLE 12 Preparation of2-(4-Chlorophenyl)-4-(3-Trifluoromethylphenoxy)Pyrimidine

3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml),is slowly added to a mixture consisting of a 4-chlorobenzamidinehydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles),potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which isstirred under reflux. When the addition of 3,3-dichloroacrolein iscompleted additional 4-chlorobenzamidine hydrochloride (1 mmoles) isadded. The reaction mixture is stirred for 3 hours under reflux andsubsequently cooled down to ambient temperature over night and filteredthrough silica. The organic phase is concentrated in vacuo. The residuewas purified by chromatography on Al₂O₃ (petrol ethers/ethyl acetate:20/1) to yield 2.79 g (80%) of the pure product having a melting pointof 92° C.

EXAMPLE 13 Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Fluorophenyl) Pyrimidine

3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml),is slowly added to a mixture consisting of a 4-fluorobenzamidine acetate(10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate(40 mmoles) nd dimethoxyethane (40 ml), which is stirred under reflux.When the addition of 3,3-dichloroacrolein is completed additional4-fluorobenzamidine acetate (1 mmoles) is added. The reaction mixture isstirred for 3 hours under reflux and subsequently cooled down to ambienttemperature over night and filtered through silica. The organic phase isconcentrated in vacuo. The residue was purified by chromatography onAl₂O₃ (petrol ethers/ethyl acetate: 20/1) to yield 2.52 g (75%) of thepure product having a melting point of 52° C.

EXAMPLE 14 Preparation of 2-Cyclopropyl-4-(3-Trifluoromethylphenoxy)Pyrimidine

3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml),is slowly added to a mixture consisting of a cyclopropylcarbamidinehydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles),potassium carbonate (40 rnmoles) and dimethyoxyethane (40 ml), which isstirred under reflux. When the addition of 3,3-dichloroacrolein iscompleted additional cyclopropylcarbamidine hydrochloride (1 mmoles) isadded. The reaction mixture is stirred for 3 hours under reflux andsubsequently cooled down to ambient temperature over night and filteredthrough silica. The organic phase is concentrated in vacuo. The residuewas purified by chromatography on Al₂O₃ (petrol ethers/ethyl acetate:20/1) to yield 2.1 g (75%) of the pure product having as a colorlessliquid; ¹H NMR (CDC1₃); δ=2.10 ppm (m, N═C(═N)═CH).

EXAMPLE 15 Preparation of2-(4-Flourophenyl)-4-(5-Trifluoromethyl2-Methylpyrazol-3-Yloxy)Pyrimidine

Water (20 mmoles) is added to a solution of1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25ml). The reaction mixture is stirred for 6{fraction (1/2 )}h at 40° C.The resulting mixture is slowly added to a mixture consisting of4-fluorobenzamidine hydrochloride (10 mmoles),4-trifluoromethyl-2-methylpyrazol-1-on (11 mmoles), potassium carbonate(60 mmoles) and dimethoxyethane (50 ml), which is stirred under reflux.When the addition of 3,3-dichloroacrolein solution is completedadditional 4-fluorobenzamidine hydrochloride (0.5 mmoles) is added. Thereaction mixture is stirred for 2 hours under reflux and subsequentlycooled down to ambient temperature. filtered through a silica, and theorganic phase is concentrated in vacuo. The residue is purified bychromatography on SiO₂ (petrol ethers/ethylacetate: 2/1) to yield 1.40 g(46%) of beige crystals having a melting point of 101-102° C.

EXAMPLE 16 Preparation of4-(2-Difluoromethoxypyridin-4-Yloxy)-2-(Pyrazin-2-yl)-Pyrimidine

Water (20 mmoles) is added to a solution of1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25ml). The mixture is stirred for 2 h at 60° C. The resulting mixture isslowly added to a mixture consisting of a pyrazine-2-carboxamidinehydrochloride (10 mmoles). 2-difluoromethoxypyridin-4-ol (10 mmoles),potassium carbonate (60 mmoles) and dimethoxyethane (50 ml), which isstirred under reflux. When the addition of 3,3-dichloroacrolein solutionis completed additional pyrazine-2-carboxamidine hydrochloride (0.5mmoles) is added. The reaction mixture is stirred for 2 hours underreflux and subsequently cooled down to ambient temperature, filteredthrough silica, and the organic phase is concentrated in vacuo. Theresidue is purified by chromatograph on SiO₂ (ethyl acetate) to yield2,60 g (82%) of beige crystals having a melting point of 128-129° C.

EXAMPLE 17 Preparation of4-(3-Trifluoromethylphenoxy)-2-(3,5-Dimethylpyrazol1-yl-Pyrimidine

Water (20 mmoles) is added to a solution of1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25ml). The mixture is stirred for 2 h at 90° C. The resulting mixture isslowly added to a mixture consisting of a3,5-dimethylpyrazole-1-carboxamidine nitrate (10 mmoles),3-trifluoromethylphenol (10 mmoles), potassium carbonate (60 mmoles) anddimethoxyethane (50 ml), which is stirred under reflux. When theaddition of 3,3-dichloroacrolein solution is completed additional3,5-dimethylpyrazole-1-carboxamidine nitrate (0.5 mmoles) is added. Thereaction mixture is stirred for 10 hours under reflux and subsequentlycooled down to ambient temperature, filtered through silica, and theorganic phase is concentrated in vacuo. The residue is purified bychromatography on SiO₂ (ethyl acetate) to give 2,2 g of a yellow solid.The solid was washed with petrol ether (50 ml) to yield 1,75 g (52%) ofcoloroless crystals having a melting point of 101-102° C.

What is claimed is:
 1. A process for the preparation of substitutedpyrimidines of formula IA

wherein R³ and R⁴ each independently represent a hydrogen atom, alkyloptionally substituted by phenyl, halogen, nitro, cyano, hydroxyl,C₁₋₄-alkoxy, C₁₋₄-haloalkoxy or C₁₋₄-alkoxycarbonyl, or representsphenyl optionally substituted by halogen, nitro, cyano, hydroxyl,C₁₋₄-alkyl, C₁₋₄alkoxy, C₁₋₄-haloalkyl, C₁₋₄-haloalkoxyC₁₋₄-haloalkylthio or halosulfanyl, and R¹ represents C₃₋₈ cycloalkyloptionally substituted by phenyl, halogen, nitro, cyano, amino,hydroxyl, C₁₋₄-alkoxy, C₁₋₄-haloalkoxy or C₁₋₄-alkoxycarbonyl, orrepresents pyrazin-2-yl optionally substituted by halogen, nitro, cyano,amino, hydroxyl, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-haloalkyl,C₁₋₄-haloalkoxy C₁₋₄-haloalkylthio or halosulfanyl, R⁵ represent ahalogen atom or a haloalkyl or haloalkoxy group and W-V represents N—CH,S—CH, N—CH—CH, CH—CH—CH or N—N(R⁶), in which R⁶ represents a C₁₋₄ alkylgroup which comprises reacting an amidine of formula II,

or a salt thereof with 3,3-dichloroacrolein in an inert solvent, in thepresence of a base and in the presence of a compound of formula IV H—X—R²  (IV), wherein X denotes oxygen and R² represents a group

and which further comprises perparing the 3,3-dichloroacrolein by anin-situ hydrolysis of a 1,1,1,3-tetrachloro-3-alkoxypropane.
 2. Acompound of formula IA

wherein R³ and R⁴ each independently represent a hydrogen atom, alkyloptionally substituted by phenyl, halogen, nitro, cyano, hydroxyl,C₁₋₄-alkoxy, C₁₋₄-haloalkoxy or C₁₋₄-alkoxycarbonyl, or represent phenyloptionally substituted by halogen, nitro, cyano, amino, hydroxyl,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-haloalkyl, C₁₋₄-haloalkoxyC₁₋₄-haloalkylthio or halosulfanyl, and R¹ represents C₃₋₈ cycloalkyloptionally substituted by phenyl, halogen, nitro, cyano, amino,hydroxyl, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-haloalkoxy orC₁₋₄-alkoxycarbonyl, or represents pyrazin-2-yl optionally substitutedby halogen, nitro, cyano, hydroxyl, C₁₋₄-alkyl, C₁₋₄-alkoxy,C₁₋₄-haloalkyl, C₁₋₄-haloalkoxy, C₁₋₄-haloalkylthio or halosulfanyl, R⁵represents a halogen atom or a haloalkyl or haloalkoxy group, and W-Vrepresents N—CH, S—CH, N—CH—CH, CH—CH—CH or N—N(R⁶), in which R⁶represents a C₁₋₄ alkyl group.